Raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these

ABSTRACT

Raloxifene acid addition salts or solvates thereof, having improved dissolution properties in media comprising hydrochloric acid are described, compared with similar preparations based on raloxifene or raloxifene hydrochloride. The disclosed acid addition salts or solvates thereof show an improved bioavailability in media comprising hydrochloric acid, such as the gastric juice. The acid addition salts or solvates thereof are addition salts or solvates of raloxifene and a pharmaceutical acceptable acid selected among succinic acid, lactic acid, malonic acid or sulphuric acid. Further, crystalline forms of the raloxifene salts and solvates thereof are disclosed. The raloxifene acid addition salts and/or solvates thereof are useful for the preparation of pharmaceutical composition for oral administration capable of fast and reliable release of the active ingredients in the stomach of the patient, in particular for the treatment of cancer or osteoporosis, or for inhibiting cartilage degradation. A new method for preparation of raloxifene lactate is also disclosed.

The invention relates to acid addition salts and/or solvates of[6-hydroxy-2-(4-hydroxyphenyl)benzol[1)]thien-3-yl][4-[2-(1-piperidinyl)-ethoxy]phenyl-,raloxifene, having high availability from media comprising dilutehydrochloric acid, such as gastric juice. In addition useful crystalforms of the acid addition salts and/or solvates are disclosed.

In another aspect the invention relates to pharmaceutical compositionfor oral administration comprising said novel acid addition salts and/orsolvates thereof, preferably in crystalline form. The pharmaceuticalcompositions according to the invention are useful because the highavailability from dilute hydrochloric acid, such as gastric juice,secures a high and reliable release of the active ingredient,raloxifene, in the stomach of the patient to whom said pharmaceuticalcomposition have been administered.

Further the invention provides an improved method for preparation andpurification of said acid addition salts and/or solvates thereof, whichmethod provides for a quick and highly efficient purification of thecrude raloxifene product.

BACKGROUND FOR THE INVENTION

Raloxifene,[6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,is a well known compound having antiestrogen and antiandrogen activity.Raloxifene or raloxifene hydrochloride has proved useful for thepreparation of pharmaceutical compositions for the treatment of cancer,osteoporosis and cartilage degradation.

Raloxifene,[6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,is also known as6-hydroxy-2-(4-hydrophenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo-[b]-thiophene.Other names for raloxifene may also be found in the literature.

EP 62 503 A1 discloses benzothiophene compounds and process forpreparing them. The disclosed compounds have antiestrogenic andantiandrogenic activity. Pharmaceutical preparation comprising saidbenzothiophene compounds are described, which preparations are usefulfor the treatment of cancers. A particular preferred compound isRaloxifene. Acid addition salts of the benzothiophene compounds withphysiologically acceptable acids are also disclosed. As examples ofphysiologically acceptable acids are mentioned among others sulphuricacid, succinic acid and lactic acid.

In the manufacture of raloxifene the crude product in the reactionmixture was evaporated to dryness, redissolved and purified in severalsteps before the pure product was recovered as a crude product that wasfurther purified to provide the desired compound.

The obtained free base was subsequent transformed into acid additionsalts using usual techniques.

EP 584 952 discloses use of raloxifene or acid addition salts thereoffor the treatment of osteoporosis. It is preferred to use an acidaddition salt of raloxifene instead of raloxifene as a free base becausethe acid addition salts generally have improved dissolution propertiescompared to the free base. As examples of acids used for the acidaddition salts are mentioned among others: hydrochloric acid, sulphuricacid, lactic acid, malonic acid and succinic acid. Raloxifenehydrochloride is the preferred acid addition salt.

EP 652 002 A1 discloses use or 2-phenyl-3-aroylbenzothiephenes orpharmaceutical acceptable acid addition salts thereof, such asraloxifene and raloxifene hydrochloride respectively, for the inhibitionof cartilage degradation.

In WO 96/09045 raloxifene hydrochloride in crystalline form or as asolvate is described.

EP 910 369 discloses raloxifene hydrochloride in crystal form where thecrystals are smaller than 50 microns, and EP 826 682 disclosesraloxifene in an amorphous form having enhanced solubility.

At present most commercial available pharmaceutical compositionscomprising raloxifene as active ingredient comprises raloxifenehydrochloride, because raloxifene hydrochloride is fairly soluble inaqueous solvents whereas raloxifene as free base is only sparinglysoluble in aqueous solvents.

Despite the extensive experimentation of increasing the bioavailabilityof raloxifene there is still a need for providing the active compound ina form having increased availability of the active compound in order toprovide pharmaceutical preparations for oral administration, whichcomposition have a high availability of the active compound raloxifenefrom the upper gastrointestinal tract.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to raloxifene acid addition salts and/orsolvates having a high availability in dilute hydrochloric acid orgastric juice.

The present inventors have surprisingly discovered that the raloxifeneacid addition salts and solvates according to the invention have highbioavailability of the active compound soon after ingestion. Inparticular the raloxifene salts and/or solvates according to theinvention have improved intrinsic dissolution properties in the presenceof hydrochloric acid such as in gastric juice, compared with thecommonly used raloxifene acid addition salt, raloxifene hydrochloride.

In a further aspect the invention relates to new and particular usefulcrystal forms of said novel raloxifene acid addition salts or solvatesthereof.

In an even further aspect the invention relates to pharmaceuticalcompositions comprising said novel raloxifene acid addition salts andsolvates thereof, which compositions after the ingestion thereof iscapable of releasing the active compound raloxifene in higher amounts,compared with the frequently used compound raloxifene hydrochloride.

A further aspect of the invention relates to a new and improved methodfor preparation of raloxifene lactate.

SHORT DESCRIPTION OF THE FIGURES

FIG. 1 shows a differential scanning calorimetric chart (DSC) forraloxifene DL-lactate. The chart was recorded at a rate of 20° C./min.

FIG. 2 shows the X-ray diffraction pattern for crystalline raloxifeneDL-lactate.

FIG. 3 shows a DSC for raloxifene L-lactate hemihydrate. The chart wasrecorded at a rate of 20° C./min.

FIG. 4 shows the X-ray diffraction pattern for crystalline raloxifeneL-lactate hemihydrate.

FIG. 5 shows a DSC for raloxifene L-lactate. The chart was recorded at arate of 20° C./min.

FIG. 6 shows the X-ray diffraction pattern for crystalline raloxifeneL-lactate.

FIG. 7 shows the Intrinsic Dissolution Rate for raloxifene succinatecompared with raloxifene hydrochloride.

FIG. 8 shows the Intrinsic Dissolution Rate for raloxifene DL-lactatecompared with raloxifene hydrochloride.

FIG. 9 shows the Intrinsic Dissolution Rate for raloxifene L-lactatecompared with raloxifene hydrochloride.

FIG. 10 shows the Intrinsic Dissolution Rate for raloxifene L-lactatehemihydrate compared with raloxifene hydrochloride.

FIG. 11 shows the Intrinsic Dissolution Rate for raloxifene malonatecompared with raloxifene hydrochloride.

FIG. 12 shows the Intrinsic Dissolution Rate for raloxifene sulphatecompared with raloxifene hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have realized that even though raloxifene hydrochloride isfairly soluble in aqueous media the solubility appear to decreasessignificant in aqueous media comprising hydrochloric acid.

By the term “dilute hydrochloric acid” or “media comprising hydrochloricacid” as used herein is meant an acidic aqueous solution containingchloride ions. Gastric juice is a preferred example of dilutehydrochloric acid.

The skilled person will appreciate that gastric juice containshydrochloric acid. Further the skilled person will appreciate that thecomposition of gastric juice apart from individual variations depends onvarious factors such as time of day, time since last meal and size andcomposition of said last meal. However for the purpose of the presentdescription, the gastric juice can be regarded as a dilute solution ofhydrochloric acid usually having a pH value in the range ofapproximately 1-3, possible also containing sodium chloride in an amountof 1-3% w/w. In the duodenum and the upper part of the small intestinesthe pH raises up to approximately 4-6 or even higher.

The raloxifene acid addition salts and/or solvates thereof according tothe invention have dissolution properties in dilute hydrochloric thatsecure a high bioavailability of these compounds. In particular thecompounds according to the invention have higher intrinsic dissolutionrates in dilute hydrochloric acid compared with free raloxifene orraloxifene hydrochloride.

The terms “high availability”, “high bioavailability” or grammaticalequivalent expressions are according to the invention intended to meanthat the raloxifene salts and/or solvates thereof are available forassimilation from the gastro intestinal tract to the circulation of thebody in high amount soon after ingestion. In particular the raloxifenesalts and/or solvates thereof have higher bioavailability compared withthe presently frequently used raloxifene compounds, i.e. raloxifene asfree base or raloxifene hydrochloride.

In accordance with the present invention the term “uppergastrointestinal tract” is intended to mean the oesophagus, the stomach,the duodenum and the upper part of the small intestines. It is believedthat the assimilation of raloxifene mainly takes place in the uppergastrointestinal tract.

The inventors have surprisingly discovered that acid addition saltsand/or solvates thereof according to the invention appear to have ahigher bioavailability from acidic solutions comprising sodium chloridecompared to raloxifene as free base or raloxifene hydrochloride incrystalline or amorphous form. Consequently, pharmaceutical preparationsfor oral administration comprising acid addition salts and/or solvatesthereof according to the invention will provide the active compoundraloxifene faster and/or in an higher amount compared withpharmaceutical preparations comprising raloxifene hydrochloride orraloxifene as free base.

Thus in one aspect the invention provides pharmaceutical preparationsfor oral administration comprising a raloxifene acid addition saltand/or solvate thereof according to the invention as the activeingredient. These preparations provide the active compound raloxifene ina form having high bioavailability when said preparations are ingestedand dispersed in gastric juice.

The high availability of the active compound secures that a therapeuticregimen using the pharmaceutical preparations according to the inventionmay be performed with higher accuracy because the attending physicianwill know that the complete dose or at least a major part thereof willbe available for assimilation from the gastro intestinal tract soonafter the ingestion the pharmaceutical preparations according to theinvention.

Therefore pharmaceutical compositions comprising such compounds mayprovide for a higher efficiency of the of said compounds by theindividuals to whom said compositions are administered, compared withcorresponding pharmaceutical compositions based on raloxifene orraloxifene hydrochloride.

Thus the pharmaceutical preparations according to the invention providea fast and high availability of the active compound in the stomach soonafter intake of the preparation.

Alternatively or additionally, the high availability of the activecompounds according to the invention may render the need formicronization superfluous, which micronization in the prior art havebeen used to increase the bioavailability of raloxifene compounds, cf.EP 910 369.

Therefore in one aspect the present invention relates to pharmaceuticalcompositions for oral administration comprising raloxifene acid additionsalts and/or solvates thereof, having fast and high bioavailability ofthe active compound raloxifene.

According to the invention the acid addition salts and/or solvates ofraloxifene is selected among the succinate, lactate, malonate or thesulphate.

The lactate may be in the D or L form or a mixture thereof such asracemic mixtures. Further the lactate may be isolated as a solvate.

Because succinic acid, malonic acid and sulphuric acid have two acidgroups per molecule, compounds of these acids and raloxifene may beisolated as either mono or di acid addition salts and/or solvatesthereof having either one or two raloxifene molecules per acid moleculerespectively.

In a preferred embodiment the acid addition salt and/or solvates thereofaccording to the invention is raloxifene DL-lactate, and in a particularpreferred embodiment the acid addition salt is raloxifene L-lactate.

The skilled person will appreciate that the acid addition saltsaccording to the invention may be isolated as solvates, which in thepresent description is to be understood as compounds where solvatemolecules are included in the solid compounds, usually in definedstoichiometric amounts.

For some compounds more that one solvate may be isolated, which solvatesdiffer only with respect of the solvent incorporated in the solid andthe number of solvate molecules per molecule of the acid addition salt.

Preferred solvates according to the invention are solvates withpharmaceutically acceptable solvents such as water or alcohols havingless than 5 carbon atoms, even more preferred selected among water,methanol, ethanol, propanol and 2-propanol.

Examples of solvates according to the invention include raloxifeneL-lactate hemihydrate, raloxifene D-lactate hemihydrate, raloxifeneDL-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifeneD-lactate ¼-hydrate, raloxifene DL-lactate ¼-hydrate and raloxifenesulphate (2-propanol solvate).

Preferred compounds according to the invention include raloxifeneD-lactate hemihydrate, raloxifene DL-lactate hemihydrate, raloxifeneL-lactate hemihydrate and raloxifene L-lactate ¼-hydrate, whereraloxifene L-lactate hemihydrate and raloxifene L-lactate ¼-hydrate isparticular preferred.

It is well known that organic compounds may be isolated in crystallineform or in amorphous form. Generally it is preferred to providecompounds in crystalline form because crystallisation usually isaccompanied by a purification of the compound, and further, becausecrystals are more well defined solids than amorphous materials theproperties of compounds in crystalline form varies less than materialsin amorphous form.

Therefore the raloxifene acid addition salts and/or solvates accordingto the invention in crystalline form provides another aspect of theinvention.

The raloxifene acid addition salts in crystalline form according to theinvention are raloxifene lactate, raloxifene malonate and raloxifenesuccinate, which all exist as distinct crystalline compounds, andraloxifene sulphate, which may be isolated in crystalline form as a2-propanol solvate having one molecule of 2-propanol incorporated pertwo raloxifene molecules.

For some of the raloxifene acid addition salts and/or solvates thereofaccording to the invention more that one crystal form may be possible,where the different crystal forms may be prepared dependent on thesolvent, temperature etc, as it will be known within the area.

Pharmaceutical preparations for oral administration comprisingraloxifene salts and/or solvates thereof according to the invention maybe prepared using pharmaceutical techniques well known within the areae.g. from text books such as Remington's manual.

For example may the raloxifene compounds according to the invention beformed for oral administration into tablets, capsules etc. In formingthe pharmaceutical preparations the compounds according to the inventionmay be mixed with usual fillers and excipients, such as disintegrationagents, lubricants, swelling agents. The preparations may also be coatedaccording to well-known techniques.

Raloxifene acid addition salts and/or solvates may be prepared usingmethods known for the skilled person.

For example may any acid addition salt be converted into the free baseand subsequently the free base may be converted into another acidaddition salt by known procedures.

Usually raloxifene is prepared directly as raloxifene hydrochloride.

The present inventors have observed that in contrast to raloxifene andpreviously tested acid addition salts thereof e.g. raloxifenehydrochloride, raloxifene lactate can easily be crystallized in highyield and high purity from an alcoholic solution.

It has been realized that this property may be used for a quick and highefficient purification of raloxifene lactate from an intermediate in thesynthesis of raloxifene.

Thus raloxifene lactate may be prepared directly without previousisolation of free raloxifene or raloxifene hydrochloride using thefollowing procedure:

To a solution of the compound having the general formula I

wherein R represents two independently selected hydroxyl protectiongroups,

in a solvent a suitable reagent is added in order to remove theprotection groups. Next the pH of the mixture is adjusted to neutralreaction using lactic acid, and thereafter raloxifene lactate may beprecipitated and isolated.

This procedure according to the invention is beneficial becauseraloxifene lactate is easily crystallized from such a mixture,particular if the solvent is an alcohol having 1-5 carbon atoms. Theeasy crystallisation of raloxifene lactate represents a high and easypurification of the raloxifene from the reaction mixture. Thecrystallized raloxifene lactate may be further purified byrecrystallization from an alcohol.

The compound having the formula I is known within the art from e.g EP875 511 A1, where it is called formula VII, and from EP 62 503, where itis prepared by the reaction scheme (B).

The group R may be any hydroxyl protection group known to the skilledperson. For example, R may be selected from C₁-C₄ alkyl, C₅-C₇cycloalkyl, benzyl —COR² or SO₂R², wherein R² is C₁-C₄ primary orsecondary alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ chloroalkyl, C₁-C₄alkylphenyl, C₁-C₄ alkoxy-phenyl, mono- or dinitrophenyl or mono- ordi(chloro or fluoro)phenyl.

The two R groups may be the same or different. It is preferred that thetwo R groups are selected so that the similar conditions are needed toremove the two groups.

The term “neutral reaction” is intended to mean that the mixture has apH value in the range of 6-8, preferably 7.0-7.5.

The chemical used to remove the protection groups may be any chemicalknown to be able to remove the particular used protection groups. It iswithin the skills of the practitioner to select a suitable chemical toremove the protection group for each selected protection group.

The solvent used for the reaction may in principle be any solvent thatis capable of dissolving the reagents and does not participate inreactions with any of the ingredients of the reaction mixture under theconditions applied. Preferred solvents are alcohols having 1 to 5 carbonatoms. Particular preferred solvents are monovalent alcohols having 1 to5 carbon atoms, where methanol, ethanol, propanol and 2-propanol are themost preferred solvents.

The obtained raloxifene lactate may be recrystallized in order to obtainthe compound in even higher purity.

As solvent for the crystallization may in principle be used any alcoholhaving suitable melting and boiling temperatures. Alcohols having 1 to 5carbon atoms and one hydroxyl group are preferred.

As examples of preferred alcohols can be mentioned methanol, ethanol,propanol, 2-propanol, butanol, 2-butanol, neobutyl alcohol, pentanol,2-pentanol and 3-pentanol.

It is within the abilities of the skilled practitioner to select asuitable solvent for crystallization of particular selected compound ofthe invention.

Ethanol is a particular preferred alcohol.

The concentration of alcohol in the crystallization mixture should behigher that 90%, preferably higher that 95%. A particular preferredsolvent for the crystallisation reaction is 96% ethanol.

The crystallisation may be performed using procedures known within thearea. Further as it will be known for the skilled person it may beadvantageous to add seeding crystals to the crystallization mixture topromote crystallisation.

Thus in another aspect the invention relates to a method forpurification of raloxifene lactate from an alcoholic solution ofraloxifene comprising addition of lactate, adjusting pH and temperatureof the obtained mixture and isolation of the formed crystallineraloxifene lactate.

In a preferred embodiment the alcoholic solution of raloxifene is thereaction mixture of the synthesis of raloxifene if necessary after achange of solvent.

The invention is further illustrated by way of examples, which aresolely provided for illustration and should not be considered atlimiting in any way.

EXAMPLES Example 1[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,succinate; Raloxifene succinate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in1250 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off. 1 L of a solutionof 70.85 g (0.6 mol) succinic acid in 2-propanol/water (80:20) is addedwith violent stirring during 1-1.5 hours. The mixture is now stirredfurther at room temperature for 18 hours, and the precipitate isfiltered off as white/yellowish crystals. The product is now washed 2times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16hours to give 178.5 g crude product.

The crude product is stirred with 890 ml of water for 3 hours and thenfiltered off and washed 3 times with 100 ml of water. The product isdried in vacuo at 55-65° C. for 16 hours to give 89.7 g (77.3% yield) ofproduct.

Mp: dec. >195° C., mp. ˜225° C.

Elemental analysis C₃₃H₃₃NO₈S:

Calculated: C, 64.96%; H, 5.62%; N, 2.37%; S, 5.42%.

Found: C, 65.64%; H, 5.49%; N, 2.60%; S, 5.99%.

IR:

3406 cm⁻¹, 3145 cm⁻¹, 2945 cm⁻¹, 2691 cm⁻¹, 1642 cm⁻¹, 1597 cm⁻¹, 1541cm⁻¹, 1501 cm⁻¹, 1457 cm⁻¹, 1430 cm⁻¹, 1421 cm⁻¹, 1356 cm⁻¹, 1259 cm⁻¹,1234 cm⁻¹, 1171 cm⁻¹, 1125 cm⁻¹, 1108 cm⁻¹, 1079 cm⁻¹, 1047 cm⁻¹, 1038cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 807 cm⁻¹, 623 cm⁻¹

XRD:

D 2Theta I(rel) I(abs)) FWHM 13.195230 6.6933 20.78 8475 0.1400 9.6956429.1137 13.43 5476 0.0300 9.304945 9.4972 18.19 7419 0.1300 8.39452310.5300 13.26 5407 0.1000 7.944460 11.1283 14.15 5768 0.1000 7.70866711.4699 17.61 7180 0.1200 7.526675 11.7482 12.32 5023 0.0898 7.32329412.0756 15.22 6205 0.1000 7.160495 12.3512 13.04 5316 0.0800 6.92681512.7696 23.68 9655 0.1300 6.606409 13.3917 29.08 11856 0.1400 6.46339213.3894 14.45 5891 0.0898 6.285432 14.0789 21.24 8662 0.1200 6.12774214.4432 63.63 25947 0.1200 5.961999 14.8469 15.55 6342 0.0900 5.87557415.0665 15.77 6430 0.0898 5.788967 15.2933 16.15 6585 0.1400 5.62422115.7441 34.74 14167 0.1200 5.453763 16.2394 22.89 9334 0.1300 5.27656016.7887 12.71 5182 0.1200 5.095057 17.3913 14.19 5786 0.1100 5.02039217.6520 11.12 4535 0.0898 4.835944 18.3309 18.30 7461 0.1200 4.76509618.6059 18.62 7591 0.1100 4.630456 19.1519 65.88 26864 0.1600 4.52551819.6003 15.16 6180 0.0800 4.484997 19.7792 24.48 9982 0.1000 4.37652820.2745 18.78 7659 0.1000 4.352225 20.3889 19.11 7790 0.1000 4.22775720.9959 29.39 11984 0.1000 4.191265 21.1808 56.82 23171 0.0800 4.15805221.3520 40.16 16377 0.0898 4.101947 21.6475 17.14 6988 0.0800 4.06206821.8626 19.79 8072 0.1000 4.010082 22.1496 11.70 4771 0.0600 3.92166022.6556 100.00 40776 0.1300 3.860487 23.0194 29.04 11842 0.1100 3.81356623.3066 19.25 7850 0.1100 3.732687 23.8189 19.33 7884 0.1300 3.69479124.0669 22.47 9161 0.1100 3.644300 24.4054 18.84 7680 0.1400 3.54407825.1067 13.63 5556 0.0700 3.496160 25.4565 16.28 6637 0.0898 3.44645825.8299 20.36 8300 0.2100 3.398344 26.2021 12.35 5036 0.1200 3.37303226.4022 8.82 3597 0.0898 3.305938 26.9481 14.08 5741 0.1100 3.28194027.1489 10.08 4112 0.0898 3.260437 27.3314 9.66 3937 0.0898 3.22708327.6194 19.22 7838 0.1200 3.179256 28.0434 16.28 6640 0.2600 3.14626928.3435 8.89 3627 0.0898 3.121159 28.5764 9.58 3907 0.0900 3.09769128.7975 10.64 4337 0.0400 3.074307 29.0213 19.64 8008 0.1200 3.03226229.4328 10.17 4148 0.1300 3.010128 29.6541 9.43 3847 0.0898

Example 2[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,malonate; Raloxifene malonate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in1250 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off. 260 ml of asolution of 62.76 g (0.6 mol) malonic acid in 2-propanol/water is addedwith violent stirring during 1-1.5 hours. The mixture is now stirredfurther at room temperature for 18 hours, and the precipitate isfiltered off as white/yellowish crystals. The product is now washed 2times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16hours to give 182.4 g crude product.

The crude product is stirred with 912 ml of water for 3 hours and thenfiltered off and dried in vacuo at 55-65° C. for 16 hours to give 98.7 g(87.2% yield) of crude product. The crude product is boiled for 5minutes in 500 ml 2-propanol and then cooled at 10° C. for 30 minutes.The product is filtered off and washed with 100 ml 2-propanol and thendried in vacuo to give 90.8 g (97%) of the product.

Mp: 226-227° C.

Elemental analysis C₃₂H₃₁NO₈S:

Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%.

Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%.

IR:

3388 cm⁻¹, 3199 cm⁻¹, 2950 cm⁻1, 2683 cm⁻¹, 2543 cm⁻¹, 1643 cm⁻¹, 1597cm⁻¹, 1539 cm⁻¹, 1502 cm⁻¹, 1467 cm⁻¹, 1421 cm⁻¹, 1355 cm⁻¹, 1306 cm⁻¹,1255 cm⁻¹, 1169 cm⁻¹, 1038 cm⁻¹, 952 cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 808 cm⁻¹,645 cm⁻¹, cm⁻¹, 623 cm⁻¹

XRD:

D 2Theta I(rel) I(abs) FWHM 14.385166 6.1391 36.51 6471 0.0100 13.1250246.7292 38.91 6896 0.1300 10.305386 8.5734 37.32 6614 0.1700 9.2792389.5236 39.85 7062 0.1300 8.860721 9.9745 34.60 6133 0.0900 8.51032810.3863 33.27 5895 0.0900 8.314361 10.6318 33.02 5852 0.0800 7.94794911.1234 41.61 7375 0.1600 7.265135 12.1727 35.79 6343 0.1300 6.88299612.8512 29.65 5254 0.0300 6.537915 13.5326 60.19 10667 0.1800 6.25825114.1404 61.12 10833 0.2100 6.003203 14.7444 31.92 5657 0.1200 5.87791115.0605 29.17 5170 0.0600 5.794580 15.2784 29.33 5198 0.0200 5.66322615.6349 49.63 8796 0.1300 5.550457 15.9547 36.61 6487 0.0800 5.35410316.5438 55.84 9897 0.2200 5.134028 17.2583 30.18 5349 0.1378 5.02384817.6397 55.21 9784 0.2100 4.836637 18.3283 36.13 6404 0.1400 4.70076118.8628 71.64 12696 0.1600 4.644808 19.0922 86.46 15323 0.1500 4.53852219.5436 61.36 10874 0.1300 4.472256 19.8361 50.40 8931 0.1000 4.34711120.4132 37.86 6709 0.1000 4.247918 20.8951 88.12 15616 0.2300 4.16142821.3344 73.93 13101 0.1600 4.085803 21.7341 37.19 6591 0.1100 4.01958422.0966 35.60 6309 0.1500 3.921695 22.6554 100.00 17722 0.1700 3.76572923.6059 50.70 8986 0.2000 3.703455 24.0097 34.79 6166 0.1200 3.63854224.4446 47.30 8382 0.1900 3.499221 25.4339 44.29 7849 0.2000 3.42687225.9801 43.63 7732 0.2200 3.292398 27.0610 23.39 4145 0.1000 3.25375527.3886 25.03 4435 0.1400 3.192249 27.9269 22.18 3931 0.1400 3.09484628.8246 28.68 5083 0.3000 3.034329 29.4123 27.30 4338 0.1900

Example 3[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,sulphate (2-propanol solvate); Raloxifene sulphate (2-propanol solvate)

3.79 g (˜0.06 mol) pulverized potassium hydroxide (>85%) is dissolved in125 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 10 g (0.0196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off A solution of 6.5g 96% (0.6 mol) sulphuric acid in 15 ml 2-propanol and 12 ml of water isadded with violent stirring during 1-1.5 hours (weakly exothermic). Themixture is now stirred further at room temperature for 18 hours, and theprecipitate is filtered off as white crystals. The product is now washed2 times with 4 ml 2-propanol and then dried in vacuo at 55-65° C. for 16hours to give 15 g crude product.

The crude product is stirred with 76 ml of water for 3 hours and thenfiltered off and washed 3 times with 100 ml of water. The product isdried in vacuo at 55-65° C. for 16 hours to give 8.6 g (% yield) ofproduct. The product is boiled with 38 ml of 2-propanol for 5 minutesand then cooled on to 0-5° C. for 30 minutes and filtered. The productis washed with 2 times with 5 ml 2-propanol, and dried in vacuum at70-75° C.

Mp: 262-263° C.

Elemental analysis C₅₉H₆₄N₂O₁₃S₃:

Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%.

Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%.

IR:

3199 cm⁻¹, 2963 cm⁻¹, 2723 cm⁻1, 2693 cm⁻¹, 2659 cm⁻¹, 2559 cm⁻¹, 1653cm⁻¹, 1597 cm⁻¹, 1547 cm⁻¹, 1501 cm⁻¹, 1467 cm⁻¹, 1437 cm⁻¹, 1419 cm⁻¹,1344 cm⁻¹, 1308 cm⁻¹, 1268 cm⁻¹, 1251 cm⁻¹, 1233 cm⁻¹, 1167 cm⁻¹, 1037cm⁻¹, 1020 cm⁻¹, 952 cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 823 cm⁻¹, 809 cm⁻¹, 627cm⁻¹, 524 cm⁻¹.

XRD:

D 2Theta I(rel) I(abs) FWHM 14.374007 6.1439 26.57 5009 0.0900 10.3037508.5748 29.62 5583 0.1300 9.201529 9.6042 26.22 4942 0.1100 8.8717269.9621 29.84 5624 0.1300 8.569965 10.3138 22.25 4195 0.0400 8.32037810.6241 25.97 4896 0.1200 7.945119 11.1274 38.65 7286 0.1300 7.51417411.7678 20.56 3876 0.1041 7.205108 12.2745 25.04 4721 0.1400 6.53743713.5336 66.78 12590 0.1400 6.228787 14.2076 21.88 4126 0.1100 5.62832915.7325 20.71 3904 0.0900 5.540447 15.9837 27.40 5166 0.1100 5.32247616.5489 64.98 12249 0.1500 5.138694 17.2425 21.65 4082 0.1100 5.02031717.6522 64.05 12074 0.1400 4.706881 18.8381 100.00 18851 0.1300 4.61809719.2036 60.47 11400 0.0800 4.538129 19.5453 59.35 11189 0.1100 4.47181619.8381 67.03 12636 0.1200 4.261964 20.8255 54.78 10327 0.1100 4.20475721.1121 51.35 9680 0.1600 4.156029 21.3625 46.65 8794 0.1041 4.09330521.6938 25.93 4888 0.0900 4.035960 22.0058 24.21 4563 0.1800 3.93718222.5651 25.37 4784 0.1200 3.835400 23.1721 22.17 4179 0.0900 3.79652823.4127 40.94 7718 0.0900 3.767170 23.5978 61.03 11505 0.1100 3.69130324.0899 20.10 3790 0.1500 3.639317 24.4393 47.20 8897 0.1200 3.59048924.7769 28.23 5321 0.1600 3.511060 25.3467 29.66 5592 0.1100 3.47858625.5873 23.70 4468 0.1041 3.416539 26.0601 37.38 7047 0.1900 3.35538926.5436 20.28 3823 0.1300 3.314637 26.8760 17.08 3220 0.1200 3.27101527.2413 15.24 2874 0.0600 3.252583 27.3987 14.71 2773 0.1041 3.10044628.7714 23.04 4344 0.1200 3.079703 28.9694 19.73 3720 0.1041 3.03382829.4172 29.23 5511 0.1300 3.009744 29.6580 15.28 2880 0.1041 2.93772530.4024 13.30 2507 0.1700

Example 4[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,DL-lactate; Raloxifene DL-lactate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in1250 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off. A solution of67.6 g 85% DL-lactic acid (0.6 mol) in 200 ml of 2-propanol is addedwith violent stirring during 1-1.5 hours. The mixture is now stirredfurther at room temperature for 18 hours, and the precipitate isfiltered off as white/yellowish crystals. The product is now washed 2times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16hours to give 109 g crude product.

The crude product is stirred with 545 ml of water for 3 hours and thenfiltered off and washed 2 times with 75 ml of water. The product isdried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) ofproduct.

Mp: 196-198° C.

Elemental analysis C₃₄H₃₃NO₇S:

Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%.

Found: C, 65.07%; H, 5.93%; N, 2.37%; S, 5.34%.

IR:

3385 cm⁻¹, 3223 cm⁻¹, 2940 cm⁻1, 2675 cm⁻¹, 1641 cm⁻¹, 1598 cm⁻¹, 1542cm⁻¹, 1502 cm⁻¹, 1467 cm⁻¹, 1421 cm⁻¹, 1349 cm⁻¹, 1307 cm⁻¹, 1253 cm⁻¹,1171 cm⁻¹, 1123 cm⁻¹, 1038 cm⁻¹, 953 cm⁻¹, 908 cm⁻¹, 837 cm⁻¹, 808 cm⁻¹,649 cm⁻¹, 623 cm⁻¹, cm⁻¹, 532 cm⁻¹, 514 cm⁻¹.

The product was further analysed using differential scanning calorimetryusing a METTLER TOLEDO STAR® system, according to the instructions ofthe manufacturer. The differential scanning calorimetric chart (DSC) isshown in FIG. 1.

Further the product was analysed by X-ray diffraction analysis using theSTOE Powder diffraction system. The result is shown in FIG. 2, and isalso listed numerically below.

XRD:

D 2Theta I(rel) I(abs) FWHM 13.595814 6.4959 28.40 12683 0.140010.855533 8.1382 16.15 7211 0.1200 9.849394 8.9711 32.17 14369 0.10009.534325 9.2682 66.95 29898 0.1300 8.150249 10.8465 45.20 20188 0.13007.240730 12.2138 63.53 28374 0.1400 6.769843 13.0670 18.42 8227 0.15006.272666 14.1077 75.67 33794 0.1900 5.818832 15.2143 13.28 5933 0.20005.657337 15.6513 18.07 8070 0.1300 5.505030 16.0872 10.51 4692 0.10005.261933 16.8357 17.48 7806 0.1400 5.089504 17.4104 16.14 7210 0.10005.001569 17.7189 41.94 18732 0.0900 4.958950 17.8725 29.16 13023 0.11484.797388 18.4795 19.39 8660 0.1100 4.669322 18.9910 49.20 21972 0.14004.574684 19.3876 63.21 28227 0.1000 4.533019 19.5676 44.94 20071 0.11484.440548 19.9792 32.70 14604 0.1200 4.301886 20.6301 100.00 44659 0.15004.155406 21.3657 78.00 34833 0.1600 4.059049 21.8797 27.53 12296 0.18003.960846 22.4285 25.59 11427 0.1000 3.907408 22.7393 83.48 37282 0.12003.865461 22.9894 16.46 7350 0.1148 3.828892 23.2120 17.46 7798 0.09003.773130 23.5599 50.71 22649 0.1200 3.716486 23.9243 23.06 10300 0.13003.652238 24.3515 15.79 7053 0.1800 3.584725 24.8174 12.91 5764 0.15003.486791 25.5261 30.45 13600 0.1200 3.439149 25.8858 22.21 9919 0.13003.396267 26.2184 17.86 7978 0.1100 3.370045 26.4261 12.48 5572 0.11483.329320 26.7553 9.21 4113 0.1100 3.292728 27.0582 11.81 5274 0.10003.278070 27.1815 11.25 5026 0.1148 3.218620 27.6935 21.24 9485 0.19003.167986 28.1452 13.80 6162 0.0900 3.143230 28.3715 30.33 13546 0.10003.095423 28.9191 14.02 6260 0.1200 3.024921 29.5058 11.56 5161 0.14003.007253 29.6831 13.40 5984 0.1300

Example 5[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,L-lactate; Raloxifene L-lactate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in1250 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off.

A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violentstirring during 1-1.5 hours. The mixture is now stirred further at roomtemperature for 18 hours, and the precipitate is filtered off aswhite/yellowish crystals. The product is now washed 2 times with 40 ml2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 109g crude product.

The crude product is stirred with 545 ml of water for 3 hours and thenfiltered off and washed 2 times with 75 ml of water. The product isdried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) ofproduct.

Mp: 134-136° C.

Elemental analysis C₃₁H₃₃NO₇S (½H₂O):

Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%.

Found: C, 65.08%; H, 6.14%; N, 2.58%; S, 5.78%.

IR:

3167 cm⁻¹, 2934 cm⁻¹, 1641 cm⁻¹, 1627 cm⁻¹, 1593 cm⁻¹, 1543 cm⁻¹, 1500cm⁻¹, 1469 cm⁻¹, 1433 cm⁻¹, 1350 cm⁻¹, 1314 cm⁻¹, 1259 cm⁻¹, 1170 cm⁻¹,1128 cm⁻¹, 1103 cm⁻¹, 1033 cm⁻¹, 908 cm⁻¹, 836 cm⁻¹, 809 cm⁻¹.

The product was analysed using differential scanning calorimetry using aMETTLER TOLEDO STAR® system, according to the instructions of themanufacturer. The differential scanning calorimetric chart (DSC) isshown in FIG. 3.

Further the product was analysed by X-ray diffraction analysis using theSTOE Powder diffraction system. The result is shown in FIG. 4, and isalso listed numerically below.

XRD:

D 2Theta I(rel) I(abs) FWHM 14.639874 6.0322 17.56 6122 0.1200 13.2074216.6871 15.07 5254 0.1200 10.875932 8.1229 80.41 28029 0.1200 9.2684569.5347 22.67 7903 0.1200 8.140638 10.8593 17.92 6247 0.1200 7.48850311.8083 15.59 5433 0.1000 7.310331 12.0971 12.47 4347 0.0800 7.08950812.4754 25.79 8991 0.1000 6.931874 12.7603 12.78 4454 0.0900 6.72393213.1566 27.83 9701 0.1300 6.551458 13.5045 14.20 4949 0.0900 6.35943213.9143 30.57 10656 0.1100 6.130010 14.4378 21.33 7435 0.1300 5.85301815.1249 36.40 12687 0.1100 5.626204 15.7385 15.49 5401 0.1300 5.50764316.0795 23.25 8106 0.1000 5.447238 16.2590 13.21 4606 0.0870 5.22444916.9573 19.21 6697 0.1100 5.160516 17.1690 17.10 5961 0.0870 5.08347517.4312 14.74 5137 0.1100 4.954247 17.8896 19.64 6848 0.1000 4.86375018.2252 28.34 9879 0.0800 4.805168 18.4494 46.26 16125 0.0700 4.75688318.6383 49.99 17425 0.0800 4.656926 19.0420 19.10 6659 0.1900 4.63019419.1530 17.96 6260 0.0870 4.566015 19.4248 21.34 7438 0.1000 4.48751419.7680 12.76 4447 0.1000 4.347753 20.4101 11.69 4074 0.1100 4.30146520.6322 19.17 6682 0.0900 4.224555 21.0120 14.55 5072 0.0870 4.18656121.2049 23.33 8134 0.1700 4.065767 21.8425 26.06 9084 0.1000 4.01556022.1190 17.10 5929 0.1000 3.976949 22.3365 14.98 5223 0.0500 3.93578522.5732 34.50 12028 0.1100 3.867038 22.9799 100.00 34859 0.1000 3.77948123.5198 40.14 13991 0.0800 3.742319 23.7567 59.68 20805 0.1000 3.71041823.9640 13.17 4591 0.0870 3.645564 24.3968 11.19 3902 0.0800 3.62180824.5593 18.71 6524 0.1000 3.552536 25.0459 16.01 5581 0.1000 3.51608825.3098 13.46 4691 0.0600 3.498357 25.4402 12.66 4413 0.0700 3.46707525.6737 10.74 3745 0.0500 3.418947 26.0414 21.49 7491 0.1000 3.39529826.2260 12.12 4225 0.0870 3.369948 26.4268 15.48 5369 0.0700 3.35855426.5181 14.33 4995 0.0600 3.244985 27.4641 11.90 4149 0.0700 3.22942727.5990 9.63 3356 0.0870 3.177657 28.0578 15.07 5253 0.1200 3.14488428.3562 32.65 11381 0.1000 3.106130 28.7176 9.83 3425 0.0800 3.08297028.9380 9.00 3138 0.0870 3.056106 29.1980 8.56 2984 0.0870 3.03218429.4335 8.74 3048 0.1100 2.994539 29.8121 8.27 2884 0.0700 2.97911429.9700 9.26 3229 0.0800 2.924922 30.5387 9.19 3203 0.1800 2.87029031.1346 16.32 5689 0.1400 2.828902 31.6019 13.59 4737 0.1100 2.76261132.3808 10.83 3775 0.1000

Example 6[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl;Raloxifene L-lactate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in1250 ml 2-propanol, with stirring and addition of nitrogen, overapproximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride isadded in small portions in such a way that temperature is kept below 30°C. After addition of raloxifene hydrochloride, the deep red suspensionis stirred for 30-45 minutes until a deep red solution appears.Reminiscence of insoluble product may be filtered off

A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violentstirring during 1-1.5 hours. The mixture is now stirred further at roomtemperature for 18 hours. If no or very little precipitate appears inthe solution the reaction mixture is filtered and 2-propanol isevaporated off. To the reminisce is now added 150 ml of water withstirring and the precipitated product is collected by filtration anddried in vacuo at 55-65° C. Next the crude product is recrystallizedfrom 160 ml 96% ethanol (if necessary seeding crystals are added) togive 62.8 g (56.4%) of the product.

Mp: 171-173° C.:

Elemental analysis C₃₁H₃₃NO₇S:

Calculated: C, 65.52%; H, 5.94%; N, 2.47%; S, 5.64%.

Found: C, 65.50%; H, 5.85%; N, 2.50%; S, 5.74%.

IR:

3159 cm⁻¹, 2935 cm⁻¹, 2806 cm⁻1, 2672 cm⁻¹, 1643 cm⁻¹, 1598 cm⁻¹, 1574cm⁻¹, 1547 cm⁻¹, 1501 cm⁻¹, 1466 cm⁻¹, 1422 cm⁻¹, 1347 cm⁻¹, 1308 cm⁻¹,1269 cm⁻¹, 1229 cm⁻¹, 1171 cm⁻¹, 1119 cm⁻¹, 1067 cm⁻¹, 1037 cm⁻¹, 1006cm⁻¹, 908 cm⁻¹, 835 cm⁻¹, 807 cm⁻¹, 665 cm⁻¹, 649 cm⁻¹, 634 cm⁻¹, 623cm⁻¹, 513 cm⁻¹.

The product was analysed using differential scanning calorimetry using aMETTLER TOLEDO STAR® system, according to the instructions of themanufacturer. The differential scanning calorimetric chart (DSC) isshown in FIG. 5.

Further the product was analysed by X-ray diffraction analysis using theSTOE Powder diffraction system. The result is shown in FIG. 6, and isalso listed numerically below.

XRD:

D 2Theta I(rel) I(abs) FWHM 14.079244 6.2726 45.93 16568 0.1300 9.9749128.8580 32.43 11699 0.1100 9.526523 9.2758 71.31 25721 0.1200 8.21559810.7600 47.82 17248 0.1100 7.246270 12.2045 80.04 28871 0.1100 7.06555712.5178 16.17 5832 0.0700 6.878001 12.8606 22.74 8201 0.1200 6.28370914.0828 66.27 23901 0.0800 6.194698 14.2862 53.98 19470 0.0984 5.85952915.1080 11.17 4028 0.0984 5.744935 15.4112 16.16 5828 0.1200 5.31222216.6751 18.02 6499 0.1200 5.046910 17.5585 34.26 12356 0.0900 4.97893317.8001 54.66 19715 0.1000 4.918535 18.0205 17.40 6277 0.0984 4.74626418.6804 26.77 9655 0.1000 4.712771 18.8143 46.35 16716 0.0900 4.56942919.4101 57.60 20777 0.1000 4.455985 19.9093 53.60 19332 0.1200 4.34558920.4204 12.70 4579 0.0900 4.268096 20.7952 86.33 31139 0.0900 4.10633221.6241 20.17 7274 0.1100 4.042283 21.9710 22.73 8197 0.1200 3.94465622.5218 23.46 8462 0.1000 3.913129 22.7056 100.00 36069 0.1100 3.83170623.1947 15.49 5586 0.0900 3.777075 23.5350 69.72 25148 0.1400 3.73587223.7983 14.85 5358 0.0984 3.667856 24.2463 11.94 4305 0.0900 3.63903524.4413 13.87 5001 0.0800 3.589918 24.7809 9.38 3383 0.0984 3.54571525.0949 23.58 8505 0.0800 3.505655 25.3864 33.63 12131 0.1100 3.44222325.8622 22.60 8152 0.1100 3.411017 26.1030 10.82 3901 0.0984 3.37185126.4117 44.16 5108 0.1000 3.280618 27.1600 15.23 5494 0.1100 3.25110427.4114 14.23 5134 0.0800 3.232072 27.5760 19.25 6943 0.1100 3.15305628.2812 12.42 4479 0.1900 3.143130 28.3724 12.29 4432 0.0984 3.08193928.9479 17.16 6189 0.2200 3.040378 29.3524 9.73 3510 0.1300 2.99050829.8532 15.29 5514 0.1400 2.929711 30.4876 11.37 4102 0.1200 2.89239730.8906 18.91 6822 0.1200 2.856192 31.2922 8.91 3214 0.1100 2.81810831.7261 14.79 5336 0.2500 2.765584 32.3450 15.86 5720 0.1300

Example 7 Preparation of[6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,L-lactate; Raloxifene L-lactate

40 g (0.06 mol) 6-methylsulphonyloxy-2-(4-methylsulphonyl-oxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,hydrochlorid, having the structural formula below

is suspended in 385 ml 2-propanol. 21.75 g (0.33 mol) powdered 85%potassium hydroxide is added with stirring, and the mixture is heated toreflux for 2 hour. The deep red solution is cooled to room temperature,and a solution of 20.3 g 85% L-lactic acid (0.18 mol) is added withviolent stirring during 1-1.5 hours, and thereafter the 2-propanol isevaporated off to give the crude product. The product is recrystallizedfrom approximately 50 ml 96% ethanol to give the title compound.

Example 8 Comparative example Dissolution of Raloxifene Hydrochloride inDilute Hydrochloric Acid or Phosphoric Acid

60 mg raloxifene HCl was transferred to a dissolution vessel containingone liter 0.1 M HCl. The mixture was vigorously mixed and left at roomtemperature over night. Subsequently the dissolution was evaluatedvisually. Very little of the initial added amount of raloxifenehydrochloride was dissolved shown by the presence of solid material atthe bottom of the vessel and essentially no colouring of the fluid.

A similar dissolution test was performed using 60 mg raloxifenehydrochloride in 0.1 M phosphoric acid. In this case all raloxifenehydrochloride seemed to be dissolved indicated by the absence of solidson the bottom of the vessel and a strong yellow colouring of the fluidin the vessel.

Example 9 Dissolution of Raloxifene Acid Addition Salts or Solvates inDilute Hydrochloric Acid or Phosphoric Acid

Using same procedures as in example 8, raloxifene succinate, raloxifeneDL-lactate, raloxifene L-lactate hemihydrate, raloxifene malonate andraloxifene sulphate (2-propanol solvate) were tested for dissolution indilute hydrochloric acid or phosphorous acid.

All these tests showed complete dissolution shown be absence of solidsin the vessel and strong colouring of the liquid.

Example 10 Intrinsic Dissolution Rate of Raloxifene Acid Addition Saltsin Dilute Phosphoric Acid Compared with Dilute Hydrochloric Acid

Experimental set-up:

The intrinsic dissolution rate of raloxifene succinate, raloxifeneDL-lactate, raloxifene L-lactate, raloxifene L-lactate hemihydrate,raloxifene malonate, raloxifene sulphate (2-propanol solvate) andraloxifene hydrochloride were tested in dilute solutions of hydrochloricacid and in dilute solutions of phosphorous acid containing NaCl inamounts so the chloride ion concentration in each solution was 0.1 M.The tests were performed at 37° C. and at pH of 1, 2, 3, 4, and 5,respectively. The raloxifene hydrochloride salt used in theseexperiments was purchased from Otto Bradt GmbH (batch MA/RF/12003) whilethe rest of the raloxifene acid additions salts were prepared accordingto Example 1-6.

The experiments were carried out following the procedure of RotationDisc Method (USP 1087) using Vankel VK 7000 Intrinsic dissolutionapparatus (Vankel Technology group, W. Vankelion) equipped with Vankel12-4120 intrinsic disc having a surface area of 0.5 cm², Vankel 12-4130surface plate, Vankel 12-4140 punch, and Vankel shaft and holder(surface area: 0.5 cm²) and operating at a rotation rate of 100 rpm.

The buffer solution is handled in a 750 ml measuring bottle, degassedand transferred into a dissolution vessel. Approximately 100 mg compoundis weighed out and transferred into an intrinsic disc. Said disc is thenassembled, and to said disc a disc is applied in the IR-press at apressure of 5 kN for 1 minute. The disc is started and samples of 10 mlare collected by use of “pressure vials” after 1, 10, 20, 30, 45, and 60minutes. The change of volume is corrected using the equation:Q=Vs×(sumCn−1)+Cn×Vtwherein Q designates the volume at the time t, C designates theconcentration of the sample n, Vt designates the volume of the liquidcollected at the time t, and Vs designates the volume of the samplecollected. The sample is measured against a standard using HPLC. Inthese measurements a 5 microns 3.9×150 mm column filled with symmetricalmaterial is employed and as eluant a 20 mM phosphate buffer KH₂PO₄, pH6.8 mixed with acetonitrile and tetrahydrofuran in the ratio 55:35:10 isused.

Preparation of Standard Solution:

The standard is prepared by use of following procedure: 20 mg of salt isdissolved initially in 100 ml of MeOH and then 1 ml of this solution istransferred to a 50 ml flask with water and then 2 ml to a 20 ml flaskof buffer in question.

Preparation of Buffer Solutions:

pH 1: a 0.1 M HCl is used.

0.025 M Phosphate buffer solution pH 2.0: 3.40 g of potassium dihydrogenphosphate is dissolved in 900 ml of water. Then pH is adjusted to 2.0with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 gof NaCl is added to 1 L of buffer.

0.025 M Phosphate buffer solution pH 3.0: 3.40 g of potassium dihydrogenphosphate is dissolved in 900 ml of water. Then pH is adjusted to 3.0with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 gof NaCl is added to 1 L of buffer.

0.022 M Phosphate buffer solution pH 4.0: 3.0 g of potassium dihydrogenphosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 Mpotassium hydroxide and phosphoric acid and diluted to 1000.0 ml withwater. Exactly 5.85 g of NaCl is added to 1 L of buffer. 0.02 MPhosphate buffer solution pH 5.0: 2.72 g of potassium dihydrogenphosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 Mpotassium hydroxide and diluted to 1000.0 ml with water. Exactly 5.85 gof NaCl is added to 1 L of buffer.

Results

The results from above described experiment comparing the ID of thevarious raloxifene acid addition salts in dilute solutions ofphosphorous acid and hydrochloric acid, respectively, is given in thetable below. The numbers in the table represent the average of twomeasurements.

DL-lactate L-lactate hemi- L-Lactate hemi- Buffer solution Succinatehydrate ¼-hydrate hydrate Malonate Sulphate Hydrochloride Hydrochloride,0.0550 0.0056 0.0035 0.0475 0.0229 0.0036 0.0022 pH 1 Phosphate, 0.02280.0119 0.0028 0.0453 0.0173 0.0137 0.0026 pH 2 Phosphate, 0.0271 0.00620.0067 0.0403 0.0148 0.0052 0.0022 pH 3 Phosphate, 0.0127 0.0212 0.03240.0190 0.0136 0.0109 0.0022 pH 4 Phosphate, 0.0119 0.0215 0.0247 0.00910.0112 0.0081 0.0044 pH 5 The intrinsic dissolution rate (IDR) in(μmol/min * cm²) of various acid addition salts of raloxifene determinedby the method described above. The numbers represent the average of twomeasurements.

Graphic displays of the results are shown in the FIGS. 7-12. The resultsshow very clearly that the intrinsic dissolution rate is markedly higherfor the raloxifene acid addition salts and/or solvates thereof accordingto the invention compared with raloxifene hydrochloride.

1. Raloxifene DL-lactate anhydrate being in crystalline form having thefollowing X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM13.595814 6.4959 28.40 12683 0.1400 10.855533 8.1382 16.15 7211 0.12009.849394 8.9711 32.17 14369 0.1000 9.534325 9.2682 66.95 29898 0.13008.150249 10.8465 45.20 20188 0.1300 7.240730 12.2138 63.53 28374 0.14006.769843 13.0670 18.42 8227 0.1500 6.272666 14.1077 75.67 33794 0.19005.818832 15.2143 13.28 5933 0.2000 5.657337 15.6513 18.07 8070 0.13005.505030 16.0872 10.51 4692 0.1000 5.261933 16.8357 17.48 7806 0.14005.089504 17.4104 16.14 7210 0.1000 5.001569 17.7189 41.94 18732 0.09004.958950 17.8725 29.16 13023 0.1148 4.797388 18.4795 19.39 8660 0.11004.669322 18.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.10004.533019 19.5676 44.94 20071 0.1148 4.440548 19.9792 32.70 14604 0.12004.301886 20.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.16004.059049 21.8797 27.53 12296 0.1800 3.960846 22.4285 25.59 11427 0.10003.907408 22.7393 83.48 37282 0.1200 3.865461 22.9894 16.46 7350 0.11483.828892 23.2120 17.46 7798 0.0900 3.773130 23.5599 50.71 22649 0.12003.716486 23.9243 23.06 10300 0.1300 3.652238 24.3515 15.79 7053 0.18003.584725 24.8174 12.91 5764 0.1500 3.486791 25.5261 30.45 13600 0.12003.439149 25.8858 22.21 9919 0.1300 3.396267 26.2184 17.86 7978 0.11003.370045 26.4261 12.48 5572 0.1148 3.329320 26.7553 9.21 4113 0.11003.292728 27.0582 11.81 5274 0.1000 3.278070 27.1815 11.25 5026 0.11483.218620 27.6935 21.24 9485 0.1900 3.167986 28.1452 13.80 6162 0.09003.143230 28.3715 30.33 13546 0.1000 3.095423 28.9191 14.02 6260 0.12003.024921 29.5058 11.56 5161 0.1400 3.007253 29.6831 13.40 5984 0.1300.


2. Raloxifene DL-lactate anhydrate being in crystalline form having thefollowing X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM9.534325 9.2682 66.95 29898 0.1300 8.150249 10.8465 45.20 20188 0.13007.240730 12.2138 63.53 28374 0.1400 6.272666 14.1077 75.67 33794 0.19004.669322 18.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.10004.301886 20.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.16003.907408 22.7393 83.48 37282 0.1200 3.773130 23.5599 50.71 22649 0.1200.


3. Raloxifene DL-lactate being in crystalline form having the followingX-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 13.5958146.4959 28.40 12683 0.1400 10.855533 8.1382 16.15 7211 0.1200 9.8493948.9711 32.17 14369 0.1000 9.534325 9.2682 66.95 29898 0.1300 8.15024910.8465 45.20 20188 0.1300 7.240730 12.2138 63.53 28374 0.1400 6.76984313.0670 18.42 8227 0.1500 6.272666 14.1077 75.67 33794 0.1900 5.81883215.2143 13.28 5933 0.2000 5.657337 15.6513 18.07 8070 0.1300 5.50503016.0872 10.51 4692 0.1000 5.261933 16.8357 17.48 7806 0.1400 5.08950417.4104 16.14 7210 0.1000 5.001569 17.7189 41.94 18732 0.0900 4.95895017.8725 29.16 13023 0.1148 4.797388 18.4795 19.39 8660 0.1100 4.66932218.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.1000 4.53301919.5676 44.94 20071 0.1148 4.440548 19.9792 32.70 14604 0.1200 4.30188620.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.1600 4.05904921.8797 27.53 12296 0.1800 3.960846 22.4285 25.59 11427 0.1000 3.90740822.7393 83.48 37282 0.1200 3.865461 22.9894 16.46 7350 0.1148 3.82889223.2120 17.46 7798 0.0900 3.773130 23.5599 50.71 22649 0.1200 3.71648623.9243 23.06 10300 0.1300 3.652238 24.3515 15.79 7053 0.1800 3.58472524.8174 12.91 5764 0.1500 3.486791 25.5261 30.45 13600 0.1200 3.43914925.8858 22.21 9919 0.1300 3.396267 26.2184 17.86 7978 0.1100 3.37004526.4261 12.48 5572 0.1148 3.329320 26.7553 9.21 4113 0.1100 3.29272827.0582 11.81 5274 0.1000 3.278070 27.1815 11.25 5026 0.1148 3.21862027.6935 21.24 9485 0.1900 3.167986 28.1452 13.80 6162 0.0900 3.14323028.3715 30.33 13546 0.1000 3.095423 28.9191 14.02 6260 0.1200 3.02492129.5058 11.56 5161 0.1400 3.007253 29.6831 13.40 5984 0.1300.


4. Raloxifene DL-lactate being in crystalline form having the followingX-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 9.5343259.2682 66.95 29898 0.1300 8.150249 10.8465 45.20 20188 0.1300 7.24073012.2138 63.53 28374 0.1400 6.272666 14.1077 75.67 33794 0.1900 4.66932218.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.1000 4.30188620.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.1600 3.90740822.7393 83.48 37282 0.1200 3.773130 23.5599 50.71 22649 0.1200.